Alzheimer's disease (AD) is a neurodegenerative disorder that is one of the most devastating and widespread diseases worldwide, mainly affecting the aging population. One of the key factors contributing to AD-related neurotoxicity is the production and aggregation of amyloid β (Aβ). Many studies have shown the ability of Aβ to bind to the cell membrane and disrupt its structure, leading to cell death. Because amyloid damage affects different parts of the brain differently, it seems likely that not only Aβ but also the nature of the membrane interface with which the amyloid interacts, helps determine the final neurotoxic effect. Because cholesterol is the dominant component of the plasma membrane, it plays an important role in Aβ-induced toxicity. Elevated cholesterol levels and their regulation by statins have been shown to be important factors influencing the progression of neurodegeneration. However, data from many studies have shown that cholesterol has both neuroprotective and aggravating effects in relation to the development of AD. In this review, we attempt to summarize recent findings on the role of cholesterol in Aβ toxicity mediated by membrane binding in the pathogenesis of AD and to consider it in the broader context of the lipid composition of cell membranes.

Department of Physiology Faculty of Science Charles University Prague Czechia

Zobrazit více v PubMed

Abe-Dohmae S., Yokoyama S. (2021). ABCA7 links sterol metabolism to the host defense system: molecular background for potential management measure of Alzheimer’s disease. Gene 768:145316. 10.1016/j.gene.2020.145316 PubMed DOI PMC

Abramov A. Y., Ionov M., Pavlov E., Duchen M. R. (2011). Membrane cholesterol content plays a key role in the neurotoxicity of β-amyloid: implications for Alzheimer’s disease. Aging Cell 10, 595–603. 10.1111/j.1474-9726.2011.00685.x PubMed DOI

Agarwal M., Khan S. (2020). Plasma lipids as biomarxers for Alzheimer’s disease: a systematic review. Cureus 12:e12008. 10.7759/cureus.12008 PubMed DOI PMC

Agrawal R. R., Montesinos J., Larrea D., Area-Gomez E., Pera M. (2020). The silence of the fats: a MAM’s story about Alzheimer. Neurobiol. Dis. 145:105062. 10.1016/j.nbd.2020.105062 PubMed DOI

Ahyayauch H., de la Arada I., Masserini M. E., Arrondo J. L. R., Goni F. M., Alonso A. (2020). The binding of Aβ42 peptide monomers to sphingomyelin/cholesterol/ganglioside bilayers assayed by density gradient ultracentrifugation. Int. J. Mol. Sci. 21:1674. 10.3390/ijms21051674 PubMed DOI PMC

Ahyayauch H., Masserini M., Goni F. M., Alonso A. (2021). The interaction of Aβ42 peptide in monomer, oligomer or fibril forms with sphingomyelin/cholesterol/ganglioside bilayers. Int. J. Biol. Macromol. 168, 611–619. 10.1016/j.ijbiomac.2020.11.112 PubMed DOI

Amaro M., Šachl R., Aydogan G., Mikhalyov I. I., Vácha R., Hof M. (2016). GM1 ganglioside inhibits β-amyloid oligomerization induced by sphingomyelin. Angew. Chem. Int. Ed. Engl. 55, 9411–9415. 10.1002/anie.201603178 PubMed DOI PMC

Anderson R. G. W., Jacobson K. (2002). Cell biology - a role for lipid shells in targeting proteins to caveolae, rafts and other lipid domains. Science 296, 1821–1825. 10.1126/science.1068886 PubMed DOI

Angelova P. R., Abramov A. Y. (2017). α-synuclein and β-amyloid - different targets, same players: calcium, free radicals and mitochondria in the mechanism of neurodegeneration. Biochem. Biophys. Res. Commun. 483, 1110–1115. 10.1016/j.bbrc.2016.07.103 PubMed DOI

Anstey K. J., Ashby-Mitchell K., Peters R. (2017). Updating the evidence on the association between serum cholesterol and risk of late-life dementia: review and meta-analysis. J. Alzheimers Dis. 56, 215–228. 10.3233/JAD-160826 PubMed DOI PMC

Arbor S. C., LaFontaine M., Cumbay M. (2016). Amyloid-β Alzheimer targets - protein processing, lipid rafts and amyloid-β pores. Yale J. Biol. Med. 89, 5–21. PubMed PMC

Area-Gomez E., de Groof A. J. C., Boldogh I., Bird T. D., Gibson G. E., Koehler C. M., et al. . (2009). Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am. J. Pathol. 175, 1810–1816. 10.2353/ajpath.2009.090219 PubMed DOI PMC

Arispe N., Doh M. (2002). Plasma membrane cholesterol controls the cytotoxicity of Alzheimer’s disease AbetaP (1–40) and (1–42) peptides. FASEB J. 16, 1526–1536. 10.1096/fj.02-0829com PubMed DOI

Ashley R. H., Harroun T. A., Hauss T., Breen K. C., Bradshaw J. P. (2006). Autoinsertion of soluble oligomers of Alzheimer’s Aβ(1–42) peptide into cholesterol-containing membranes is accompanied by relocation of the sterol towards the bilayer surface. BMC Struct. Biol. 6:21. 10.1186/1472-6807-6-21 PubMed DOI PMC

Audagnotto M., Lorkowski A. K., Dal Peraro M. (2018). Recruitment of the amyloid precursor protein by γ-secretase at the synaptic plasma membrane. Biochem. Biophys. Res. Commun. 498, 334–341. 10.1016/j.bbrc.2017.10.164 PubMed DOI

Avdulov N. A., Chochina S. V., Igbavboa U., Warden C. S., Vassiliev A. V., Wood W. G. (1997). Lipid binding to amyloid β-peptide aggregates: preferential binding of cholesterol as compared with phosphatidylcholine and fatty acids. J. Neurochem. 69, 1746–1752. 10.1046/j.1471-4159.1997.69041746.x PubMed DOI

Azouz M., Cullin C., Lecomte S., Lafleur M. (2019). Membrane domain modulation of Aβ1-42 oligomer interactions with supported lipid bilayers: an atomic force microscopy investigation. Nanoscale 11, 20857–20867. 10.1039/c9nr06361g PubMed DOI

Baldwin A. J., Knowles T. P. J., Tartaglia G. G., Fitzpatrick A. W., Devlin G. L., Shammas S. L., et al. . (2011). Metastability of native proteins and the phenomenon of amyloid formation. J. Am. Chem. Soc. 133, 14160–14163. 10.1021/ja2017703 PubMed DOI

Banerjee S., Hashemi M., Zagorski K., Lyubchenko Y. L. (2021). Cholesterol in membranes facilitates aggregation of amyloid β protein at physiologically relevant concentrations. ACS Chem. Neurosci. 12, 506–516. 10.1021/acschemneuro.0c00688 PubMed DOI

Barbero-Camps E., Fernandez A., Martinez L., Fernandez-Checa J. C., Colell A. (2013). APP/PS1 mice overexpressing SREBP-2 exhibit combined Aβ accumulation and tau pathology underlying Alzheimer’s disease. Hum. Mol. Gen. 22, 3460–3476. 10.1093/hmg/ddt201 PubMed DOI PMC

Barbero-Camps E., Roca-Agujetas V., Bartolessis I., de Dios C., Fernandez-Checa J. C., Mari M., et al. . (2018). Cholesterol impairs autophagy-mediated clearance of amyloid β while promoting its secretion. Autophagy 14, 1129–1154. 10.1080/15548627.2018.1438807 PubMed DOI PMC

Barrett M. A., Alsop R. J., Hauss T., Rheinstadter M. C. (2015). The position of Aβ22-40 and Aβ1-42 in anionic lipid membranes containing cholesterol. Membranes (Basel) 5, 824–843. 10.3390/membranes5040824 PubMed DOI PMC

Barrett P. J., Song Y. L., Van Horn W. D., Hustedt E. J., Schafer J. M., Hadziselimovic A., et al. . (2012). The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336, 1168–1171. 10.1126/science.1219988 PubMed DOI PMC

Beel A. J., Sakakura M., Barrett P. J., Sanders C. R. (2010). Direct binding of cholesterol to the amyloid precursor protein: an important interaction in lipid-Alzheimer’s disease relationships? Biochim. Biophys. Acta 1801, 975–982. 10.1016/j.bbalip.2010.03.008 PubMed DOI PMC

Belkouch M., Hachem M., Elgot A., Lo Van A., Picq M., Guichardant M., et al. . (2016). The pleiotropic effects of omega-3 docosahexaenoic acid on the hallmarks of Alzheimer’s disease. J. Nutr. Biochem 38, 1–11. 10.1016/j.jnutbio.2016.03.002 PubMed DOI

Bennett E. E., Gianattasio K. Z., Hughes T. M., Mosley T. H., Wong D. F., Gottesman R. F., et al. . (2020). The association between midlife lipid levels and late-life brain amyloid deposition. Neurobiol. Aging 92, 73–74. 10.1016/j.neurobiolaging.2020.03.015 PubMed DOI PMC

Bera S., Arad E., Schnaider L., Shaham-Niv S., Castelletto V., Peretz Y., et al. . (2019). Unravelling the role of amino acid sequence order in the assembly and function of the amyloid-β core. Chem. Commun. (Camb) 55, 8595–8598. 10.1039/c9cc03654g PubMed DOI

Bode D. C., Baker M. D., Viles J. H. (2017). Ion channel formation by amyloid-β42 oligomers but not amyloid-β40 in cellular membranes. J. Biol. Chem. 292, 1404–1413. 10.1074/jbc.M116.762526 PubMed DOI PMC

Bodovitz S., Klein W. L. (1996). Cholesterol modulates α-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 271, 4436–4440. 10.1074/jbc.271.8.4436 PubMed DOI

Boisvert M. M., Erikson G. A., Shokhirev M. N., Allen N. J. (2018). The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 22, 269–285. 10.1016/j.celrep.2017.12.039 PubMed DOI PMC

Braak H., Braak E. (1997). Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357. 10.1016/s0197-4580(97)00056-0 PubMed DOI

Braak H., Thal D. R., Ghebremedhin E., Del Tredici K. (2011). Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969. 10.1097/NEN.0b013e318232a379 PubMed DOI

Brown R. E. (1998). Sphingolipid organization in biomembranes: what physical studies of model membranes reveal. J. Cell Sci. 111, 1–9. 10.1242/jcs.111.1.1 PubMed DOI PMC

Brown A. M., Bevan D. R. (2016). Molecular dynamics simulations of amyloid β-peptide (1–42): tetramer formation and membrane interactions. Biophys. J. 111, 937–949. 10.1016/j.bpj.2016.08.001 PubMed DOI PMC

Brown A. M., Bevan D. R. (2017). Influence of sequence and lipid type on membrane perturbation by human and rat amyloid β-peptide (1–42). Arch. Biochem. Biophys. 614, 1–13. 10.1016/j.abb.2016.11.006 PubMed DOI

Bucciantini M., Rigacci S., Stefani M. (2014). Amyloid aggregation: role of biological membranes and the aggregate-membrane system. J. Phys. Chem. Lett. 5, 517–527. 10.1021/jz4024354 PubMed DOI

Burns M. P., Igbavboa U., Wang L. L., Wood W. G., Duff K. (2006). Cholesterol distribution, not total levels, correlate with altered amyloid precursor, protein processing in statin-treated mice. Neuromol. Med. 8, 319–328. 10.1385/nmm:8:3:319 PubMed DOI

Burns M. P., Noble W. J., Olm V., Gaynor K., Casey E., LaFrancois J., et al. . (2003). Co-localization of cholesterol, apolipoprotein E and fibrillar Aβ in amyloid plaques. Brain Res. Mol. Brain Res. 110, 119–125. 10.1016/s0169-328x(02)00647-2 PubMed DOI

Carlsson C. M., Gleason C. E., Hess T. M., Moreland K. A., Blazel H. M., Koscik R. L., et al. . (2008). Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimer’s disease. J. Alzheimers Dis. 13, 187–197. 10.3233/jad-2008-13209 PubMed DOI

Carrotta R., Mangione M. R., Librizzi F., Moran O. (2021). Small angle X-ray scattering sensing membrane composition: the role of sphingolipids in membrane-amyloid β-peptide interaction. Biology (Basel) 11:26. 10.3390/biology11010026 PubMed DOI PMC

Cecchi C., Nichino D., Zampagni M., Bernacchioni C., Evangelisti E., Pensalfini A., et al. . (2009). A protective role for lipid raft cholesterol against amyloid-induced membrane damage in human neuroblastoma cells. Biochim. Biophys. Acta 1788, 2204–2216. 10.1016/j.bbamem.2009.07.019 PubMed DOI

Cecchi C., Stefani M. (2013). The amyloid-cell membrane system. The interplay between the biophysical features of oligomers/fibrils and cell membrane defines amyloid toxicity. Biophys. Chem. 182, 30–43. 10.1016/j.bpc.2013.06.003 PubMed DOI

Chan R. B., Oliveira T. G., Cortes E. P., Honig L. S., Duff K. E., Small S. A., et al. . (2012). Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J. Biol. Chem. 287, 2678–2688. 10.1074/jbc.M111.274142 PubMed DOI PMC

Chang T. Y., Yamauchi Y., Hasan M. T., Chang C. (2017). Cellular cholesterol homeostasis and Alzheimer’s disease. J. Lipid Res. 58, 2239–2254. 10.1194/jlr.R075630 PubMed DOI PMC

Chen G. F., Xu T. H., Yan Y., Zhou Y. R., Jiang Y., Melcher K., et al. . (2017). Amyloid β: structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 38, 1205–1235. 10.1038/aps.2017.28 PubMed DOI PMC

Cheng S. W., Cao D. F., Hottman D. A., Yuan L. L., Bergo M. O., Li L. (2013). Farnesyltransferase haplodeficiency reduces neuropathology and rescues cognitive function in a mouse model of Alzheimer disease. J. Biol. Chem. 288, 35952–35960. 10.1074/jbc.M113.503904 PubMed DOI PMC

Cheng H., Wang M., Li J. L., Cairns N. J., Han X. (2013). Specific changes of sulfatide levels in individuals with preclinical Alzheimer’s disease: an early event in disease pathogenesis. J. Neurochem. 127, 733–738. 10.1111/jnc.12368 PubMed DOI PMC

Chew H., Solomon V. A., Fonteh A. N. (2020). Involvement of lipids in Alzheimer’s disease pathology and potential therapies. Front. Physiol. 11:598. 10.3389/fphys.2020.00598 PubMed DOI PMC

Cho H., Choi J. Y., Hwang M. S., Kim Y. J., Lee H. M., Lee H. S., et al. . (2016). in vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann. Neurol. 80, 247–258. 10.1002/ana.24711 PubMed DOI

Chochina S. V., Avdulov N. A., Igbavboa U., Cleary J. P., O’Hare E. O., Wood W. G. (2001). Amyloid β-peptide1-40 increases neuronal membrane fluidity: role of cholesterol and brain region. J. Lipid Res. 42, 1292–1297. PubMed

Choucair A., Chakrapani M., Chakravarthy B., Katsaras J., Johnston L. J. (2007). Preferential accumulation of Aβ(1–42) on gel phase domains of lipid bilayers: an AFM and fluorescence study. Biochim. Biophys. Acta 1768, 146–154. 10.1016/j.bbamem.2006.09.005 PubMed DOI

Chow V. W., Mattson M. P., Wong P. C., Gleichmann M. (2010). An overview of app processing enzymes and products. Neuromol. Med. 12, 1–12. 10.1007/s12017-009-8104-z PubMed DOI PMC

Chung H. S., Lee J. S., Kim J. A., Roh E., Lee Y. B., Hong S. H., et al. . (2019). Variability in total cholesterol concentration is associated with the risk of dementia: a nationwide population-based cohort study. Front. Neurol. 10:441. 10.3389/fneur.2019.00441 PubMed DOI PMC

Chung J., Phukan G., Vergote D., Mohamed A., Maulik M., Stahn M., et al. . (2018). Endosomal-lysosomal cholesterol sequestration by U18666A differentially regulates amyloid precursor protein (APP) metabolism in normal and APP-overexpressing cells. Mol. Cell. Biol. 38, e00529–e00617. 10.1128/MCB.00529-17 PubMed DOI PMC

Ciudad S., Puig E., Botzanowski T., Meigooni M., Arango A. S., Do J., et al. . (2020). Aβ1–42 tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage. Nat. Commun. 11:3014. 10.1038/s41467-020-16566-1 PubMed DOI PMC

Cordy J. M., Hussain I., Dingwall C., Hooper N. M., Turner A. J. (2003). Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. U S A 100, 11735–11740. 10.1073/pnas.1635130100 PubMed DOI PMC

Cossec J. C., Simon A., Marquer C., Moldrich R. X., Leterrier C., Rossier J., et al. . (2010). Clathrin-dependent APP endocytosis and Aβ secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim. Biophys. Acta 1801, 846–852. 10.1016/j.bbalip.2010.05.010 PubMed DOI

Cuco A., Serro A. P., Farinha J. P., Saramago B., da Silva A. G. (2016). Interaction of the Alzheimer Aβ(25–35) peptide segment with model membranes. Colloids Surf. B Biointerfaces 141, 10–18. 10.1016/j.colsurfb.2016.01.015 PubMed DOI

Curtain C. C., Ali F. E., Smith D. G., Bush A. I., Masters C. L., Barnham K. J. (2003). Metal ions, pH and cholesterol regulate the interactions of Alzheimer’s disease amyloid-β peptide with membrane lipid. J. Biol. Chem. 278, 2977–2982. 10.1074/jbc.M205455200 PubMed DOI

Czuba E., Steliga A., Lietzau G., Kowianski P. (2017). Cholesterol as a modifying agent of the neurovascular unit structure and function under physiological and pathological conditions. Metabol. Brain Dis. 32, 935–948. 10.1007/s11011-017-0015-3 PubMed DOI PMC

Dai Y. P., Zhang M. X., Shi X. L., Wang K., Gao G. B., Shen L., et al. . (2020). Kinetic study of Aβ(1–42) amyloidosis in the presence of ganglioside-containing vesicles. Colloids Surf. B Biointerfaces 185:110615. 10.1016/j.colsurfb.2019.110615 PubMed DOI

Dai L. J., Zou L., Meng L. X., Qiang G. F., Yan M. M., Zhang Z. T. (2021). Cholesterol metabolism in neurodegenerative diseases: molecular mechanisms and therapeutic targets. Mol. Neurobiol. 58, 2183–2201. 10.1007/s12035-020-02232-6 PubMed DOI

Daneschvar H. L., Aronson M. D., Smetana G. W. (2015). Do statins prevent Alzheimer’s disease? A narrative review. Eur. J. Int. Med. 26, 666–669. 10.1016/j.ejim.2015.08.012 PubMed DOI

Dante S., Hauss T., Dencher N. A. (2006). Cholesterol inhibits the insertion of the Alzheimer’s peptide Aβ(25–35) in lipid bilayers. Eur. Biophys. J. 35, 523–531. 10.1007/s00249-006-0062-x PubMed DOI

Das A., Brown M. S., Anderson D. D., Goldstein J. L., Radhakrishnan A. (2014). Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis. eLife 3:e02882. 10.7554/eLife.02882 PubMed DOI PMC

de Leeuw S. M., Kirschner A. W. T., Lindner K., Rust R., Budny V., Wolski W. E., et al. . (2022). APOE2, E3 and E4 differentially modulate cellular homeostasis, cholesterol metabolism and inflammatory response in isogenic iPSC-derived astrocytes. Stem Cell Rep. 17, 110–126. 10.1016/j.stemcr.2021.11.007 PubMed DOI PMC

de Oliveira F. F., Chen E. S., Smith M. C., Bertolucci P. H. F. (2017). Longitudinal lipid profile variations and clinical change in Alzheimer’s disease dementia. Neurosci. Lett. 646, 36–42. 10.1016/j.neulet.2017.03.003 PubMed DOI

Decock M., El Haylani L., Stanga S., Dewachter I., Octave J. N., Smith S. O., et al. . (2015). Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing. FEBS Open. Bio. 5, 763–773. 10.1016/j.fob.2015.09.002 PubMed DOI PMC

DelBove C. E., Strothman C. E., Lazarenko R. M., Huang H., Sanders C. R., Zhang Q. (2019). Reciprocal modulation between amyloid precursor protein and synaptic membrane cholesterol revealed by live cell imaging. Neurobiol. Dis. 127, 449–461. 10.1016/j.nbd.2019.03.009 PubMed DOI PMC

D’Errico G., Vitiello G., Ortona O., Tedeschi A., Ramunno A., D’Ursi A. M. (2008). Interaction between Alzheimer’s Aβ(25–35) peptide and phospholipid bilayers: the role of cholesterol. Biochim. Biophys. Acta 1778, 2710–2716. 10.1016/j.bbamem.2008.07.014 PubMed DOI

Devanathan S., Salamon Z., Lindblom G., Grobner G., Tollin G. (2006). Effects of sphingomyelin, cholesterol and zinc ions on the binding, insertion and aggregation of the amyloid Aβ1-40 peptide in solid-supported lipid bilayers. FEBS J. 273, 1389–1402. 10.1111/j.1742-4658.2006.05162.x PubMed DOI

Di Paolo G., Kim T. W. (2011). Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat. Rev. Neurosci. 12, 284–296. 10.1038/nrn3012 PubMed DOI PMC

Di Scala C., Troadec J. D., Lelievre C., Garmy N., Fantini J., Chahinian H. (2014). Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer β-amyloid peptide. J. Neurochem. 128, 186–195. 10.1111/jnc.12390 PubMed DOI

Di Scala C., Yahi N., Boutemeur S., Flores A., Rodriguez L., Chahinian H., et al. . (2016). Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein. Sci. Rep. 6:28781. 10.1038/srep28781 PubMed DOI PMC

Di Scala C., Yahi N., Lelievre C., Garmy N., Chahinian H., Fantini J. (2013). Biochemical identification of a linear cholesterol-binding domain within Alzheimer’s β amyloid peptide. ACS Chem. Neurosci. 4, 509–517. 10.1021/cn300203a PubMed DOI PMC

Diaz M., Fabelo N., Ferrer I., Marin R. (2018). “Lipid raft aging” in the human frontal cortex during nonpathological aging: gender influences and potential implications in Alzheimer’s disease. Neurobiol. Aging 67, 42–52. 10.1016/j.neurobiolaging.2018.02.022 PubMed DOI

Diaz M., Fabelo N., Martin V., Ferrer I., Gomez T., Marin R. (2015). Biophysical alterations in lipid rafts from human cerebral cortex associate with increased BACE1/AβPP interaction in early stages of Alzheimer’s disease. J. Alzheimers Dis. 43, 1185–1198. 10.3233/JAD-141146 PubMed DOI

Dies H., Toppozini L., Rheinstadter M. C. (2014). The interaction between amyloid-β peptides and anionic lipid membranes containing cholesterol and melatonin. PLoS One 9:e99124. 10.1371/journal.pone.0099124 PubMed DOI PMC

Dietschy J. M., Turley S. D. (2004). Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J. Lipid Res. 45, 1375–1397. 10.1194/jlr.R400004-JLR200 PubMed DOI

Ding H., Schauerte J. A., Steel D. G., Gafni A. (2012). β-amyloid (1–40) peptide interactions with supported phospholipid membranes: a single-molecule study. Biophys. J. 103, 1500–1509. 10.1016/j.bpj.2012.08.051 PubMed DOI PMC

Distl R., Meske V., Ohm T. G. (2001). Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol. 101, 547–554. 10.1007/s004010000314 PubMed DOI

Djelti F., Braudeau J., Hudry E., Dhenain M., Varin J., Bieche I., et al. . (2015). CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease. Brain 138, 2383–2398. 10.1093/brain/awv166 PubMed DOI

Dong X. W., Sun Y. X., Wei G. H., Nussinov R., Ma B. Y. (2017). Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning. Phys. Chem. Chem. Phys. 19, 27556–27569. 10.1039/c7cp05959k PubMed DOI PMC

Drolle E., Gaikwad R. M., Leonenko Z. (2012). Nanoscale electrostatic domains in cholesterol-laden lipid membranes create a target for amyloid binding. Biophys. J. 103, L27–L29. 10.1016/j.bpj.2012.06.053 PubMed DOI PMC

Eckert G. P., Cairns N. J., Maras A., Gattaz W. F., Muller W. E. (2000). Cholesterol modulates the membrane-disordering effects of β-amyloid peptides in the hippocampus: specific changes in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 11, 181–186. 10.1159/000017234 PubMed DOI

Eckert G. P., Wood W. G., Muller W. E. (2001). Effects of aging and β-amyloid on the properties of brain synaptic and mitochondrial membranes. J. Neural Transm. (Vienna) 108, 1051–1064. 10.1007/s007020170024 PubMed DOI

Egawa J., Pearn M. L., Lemkuil B. P., Patel P. M., Head B. P. (2016). Membrane lipid rafts and neurobiology: age-related changes in membrane lipids and loss of neuronal function. J. Physiol. 594, 4565–4579. 10.1113/JP270590 PubMed DOI PMC

Ehehalt R., Keller P., Haass C., Thiele C., Simons K. (2003). Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts. J. Cell Biol. 160, 113–123. 10.1083/jcb.200207113 PubMed DOI PMC

Elias P. K., Elias M. F., D’Agostino R. B., Sullivan L. M., Wolf P. A. (2005). Serum cholesterol and cognitive performance in the Framingham heart study. Psychosom. Med. 67, 24–30. 10.1097/01.psy.0000151745.67285.c2 PubMed DOI

Emre C., Do K.V., Jun B., Hjorth E., Alcalde S.G., Kautzmann M.I., et al. . (2021). Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 9:116. 10.1186/s40478-021-01216-4 PubMed DOI PMC

Evangelisti E., Cascella R., Becatti M., Marrazza G., Dobson C. M., Chiti F., et al. . (2016). Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases. Sci. Rep. 6:32721. 10.1038/srep32721 PubMed DOI PMC

Evangelisti E., Zampagni M., Cascella R., Becatti M., Fiorillo C., Caselli A., et al. . (2014). Plasma membrane injury depends on bilayer lipid composition in Alzheimer’s disease. J. Alzheimers Dis. 41, 289–300. 10.3233/JAD-131406 PubMed DOI

Ewald M., Henry S., Lambert E., Feuillie C., Bobo C., Cullin C., et al. . (2019). High speed atomic force microscopy to investigate the interactions between toxic Aβ1–42 peptides and model membranes in real time: impact of the membrane composition. Nanoscale 11, 7229–7238. 10.1039/c8nr08714h PubMed DOI

Fabelo N., Martin V., Marin R., Moreno D., Ferrer I., Diaz M. (2014). Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer’s disease and facilitates APP/BACE1 interactions. Neurobiol. Aging 35, 1801–1812. 10.1016/j.neurobiolaging.2014.02.005 PubMed DOI

Fabelo N., Martín V., Marín R., Santpere G., Aso E., Ferrer I., et al. . (2012). Evidence for premature lipid raft aging in APP/PS1 double-transgenic mice, a model of familial Alzheimer disease. J. Neuropathol. Exp. Neurol. 71, 868–881. 10.1097/NEN.0b013e31826be03c PubMed DOI

Fabiani C., Antollini S. S. (2019). Alzheimer’s disease as a membrane disorder: spatial cross-talk among β-amyloid peptides, nicotinic acetylcholine receptors and lipid rafts. Front. Cell. Neurosci. 13:309. 10.3389/fncel.2019.00309 PubMed DOI PMC

Fang E. F., Hou Y. J., Palikaras K., Adriaanse B. A., Kerr J. S., Yang B. M., et al. . (2019). Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412. 10.1038/s41593-018-0332-9 PubMed DOI PMC

Fantini J., Chahinian H., Yahi N. (2020). Progress toward Alzheimer’s disease treatment: leveraging the Achilles’ heel of Aβ oligomers? Protein Sci. 29, 1748–1759. 10.1002/pro.3906 PubMed DOI PMC

Fantini J., Di Scala C., Baier C. J., Barrantes F. J. (2016). Molecular mechanisms of protein-cholesterol interactions in plasma membranes: functional distinction between topological (tilted) and consensus (CARC/CRAC) domains. Chem. Phys. Lipids 199, 52–60. 10.1016/j.chemphyslip.2016.02.009 PubMed DOI

Fantini J., Di Scala C., Yahi N., Troadec J. D., Sadelli K., Chahinian H., et al. . (2014). Bexarotene blocks calcium-permeable ion channels formed by neurotoxic Alzheimer’s β-amyloid peptides. ACS Chem. Neurosci. 5, 216–224. 10.1021/cn400183w PubMed DOI PMC

Fantini J., Yahi N. (2010). Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases. Exp. Rev. Mol. Med. 12:e27. 10.1017/S1462399410001602 PubMed DOI PMC

Farooqui A. A., Rapoport S. I., Horrocks L. A. (1997). Membrane phospholipid alterations in Alzheimer’s disease: deficiency of ethanolamine plasmalogens. Neurochem. Res. 22, 523–527. 10.1023/a:1027380331807 PubMed DOI

Fassbender K., Simons M., Bergmann C., Stroick M., Lutjohann D., Keller P., et al. . (2001). Simvastatin strongly reduces levels of Alzheimer’s disease β-amyloid peptides Aβ 42 and Aβ 40 in vitro and in vivo. Proc. Natl. Acad. Sci. U S A 98, 5856–5861. 10.1073/pnas.081620098 PubMed DOI PMC

Fernandez C. G., Hamby M. E., McReynolds M. L., Ray W. J. (2019). The role of APOE4 in disrupting the homeostatic functions of astrocytes and microglia in aging and Alzheimer’s disease. Front. Aging Neurosci. 11:14. 10.3389/fnagi.2019.00014 PubMed DOI PMC

Fernandez A., Llacuna L., Fernandez-Checa J. C., Colell A. (2009). Mitochondrial cholesterol loading exacerbates amyloid β peptide-induced inflammation and neurotoxicity. J. Neurosci. 29, 6394–6405. 10.1523/JNEUROSCI.4909-08.2009 PubMed DOI PMC

Fernandez-Perez E. J., Sepulveda F. J., Peters C., Bascunan D., Riffo-Lepe N. O., Gonzalez-Sanmiguel J., et al. . (2018). Effect of cholesterol on membrane fluidity and association of Aβ oligomers and subsequent neuronal damage: a double-edged sword. Front. Aging Neurosci. 10:226. 10.3389/fnagi.2018.00226 PubMed DOI PMC

Ferris H. A., Perry R. J., Moreira G. V., Shulman G. I., Horton J. D., Kahn C. R. (2017). Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc. Natl. Acad. Sci. U S A 114, 1189–1194. 10.1073/pnas.1620506114 PubMed DOI PMC

Fitz N. F., Cronican A., Pham T., Fogg A., Fauq A. H., Chapman R., et al. . (2010). Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice. J. Neurosci. 30, 6862–6872. 10.1523/JNEUROSCI.1051-10.2010 PubMed DOI PMC

Fraering P. C., Ye W. J., Strub J. M., Dolios G., LaVoie M. J., Ostaszewski B. L., et al. . (2004). Purification and characterization of the human γ-secretase complex. Biochemistry 43, 9774–9789. 10.1021/bi0494976 PubMed DOI

Frank C., Rufini S., Tancredi V., Forcina R., Grossi D., D’Arcangelo G. (2008). Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus. Exp. Neurol. 212, 407–414. 10.1016/j.expneurol.2008.04.019 PubMed DOI

Frankel D., Davies M., Bhushan B., Kulaberoglu Y., Urriola-Munoz P., Bertrand-Michel J., et al. . (2020). Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid β-induced damage in vitro. Aging (Albany NY) 12, 22266–22290. 10.18632/aging.202138 PubMed DOI PMC

Fukui K., Ferris H. A., Kahn C. R. (2015). Effect of cholesterol reduction on receptor signaling in neurons. J. Biol. Chem. 290, 26383–26392. 10.1074/jbc.M115.664367 PubMed DOI PMC

Gao Q., Wu G. F., Lai K. W. C. (2020). Cholesterol modulates the formation of the Aβ ion channel in lipid bilayers. Biochemistry 59, 992–998. 10.1021/acs.biochem.9b00968 PubMed DOI

Ghribi O., Larsen B., Schrag M., Herman M. M. (2006). High cholesterol content in neurons increases BACE, β-amyloid and phosphorylated tau levels in rabbit hippocampus. Exp. Neurol. 200, 460–467. 10.1016/j.expneurol.2006.03.019 PubMed DOI

Grassi S., Giussani P., Mauri L., Prioni S., Sonnino S., Prinetti A. (2020). Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases. J. Lipid Res. 61, 636–654. 10.1194/jlr.TR119000427 PubMed DOI PMC

Green R. C., McNagny S. E., Jayakumar P., Cupples L. A., Benke K., Farrer L. A., et al. . (2006). Statin use and the risk of Alzheimer’s disease: the MIRAGE study. Alzheimers Dement. 2, 96–103. 10.1016/j.jalz.2006.02.003 PubMed DOI

Grouleff J., Irudayam S. J., Skeby K. K., Schiott B. (2015). The influence of cholesterol on membrane protein structure, function and dynamics studied by molecular dynamics simulations. Biochim. Biophys. Acta 1848, 1783–1795. 10.1016/j.bbamem.2015.03.029 PubMed DOI

Gylys K. H., Fein J. A., Yang F., Miller C. A., Cole G. M. (2007). Increased cholesterol in Aβ-positive nerve terminals from Alzheimer’s disease cortex. Neurobiol. Aging 28, 8–17. 10.1016/j.neurobiolaging.2005.10.018 PubMed DOI

Haag M. D. M., Hofman A., Koudstaal P. J., Stricker B. H. C., Breteler M. M. B. (2009). Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam study. J. Neurol. Neurosurg. Psych. 80, 13–17. 10.1136/jnnp.2008.150433 PubMed DOI

Habchi J., Chia S., Galvagnion C., Michaels T. C. T., Bellaiche M. M. J., Ruggeri F. S., et al. . (2018). Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. Nat. Chem. 10, 673–683. 10.1038/s41557-018-0031-x PubMed DOI

Harris J. R. (2008). Cholesterol binding to amyloid-β fibrils: a TEM study. Micron 39, 1192–1196. 10.1016/j.micron.2008.05.001 PubMed DOI

Hashimoto M., Katakura M., Hossain S., Rahman A., Shimada T., Shido O. (2011). Docosahexaenoic acid withstands the Aβ25–35-induced neurotoxicity in SH-SY5Y cells. J. Nutr. Biochem. 22, 22–29. 10.1016/j.jnutbio.2009.11.005 PubMed DOI

Hayashi H., Igbavboa U., Hamanaka H., Kobayashi M., Fujita S. C., Wood W. G., et al. . (2002). Cholesterol is increased in the exofacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice. Neuroreport 13, 383–386. 10.1097/00001756-200203250-00004 PubMed DOI

Henry S., Bercu N. B., Bobo C., Cullin C., Molinari M., Lecomte S. (2018). Interaction of Aβ1–42 peptide or their variant with model membrane of different composition probed by infrared nanospectroscopy. Nanoscale 10, 936–940. 10.1039/c7nr07489a PubMed DOI

Hernandez P., Lee G., Sjoberg M., Maccioni R. B. (2009). Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ25–35: involvement of lipid rafts. J. Alzheimers Dis. 16, 149–156. 10.3233/JAD-2009-0933 PubMed DOI

Heverin M., Bogdanovic N., Lutjohann D., Bayer T., Pikuleva I., Bretillon L., et al. . (2004). Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer’s disease. J. Lipid Res. 45, 186–193. 10.1194/jlr.M300320-JLR200 PubMed DOI

Hicks D. A., Nalivaeva N. N., Turner A. J. (2012). Lipid rafts and Alzheimer’s disease: protein-lipid interactions and perturbation of signaling. Front. Physiol. 3:189. 10.3389/fphys.2012.00189 PubMed DOI PMC

Hirai M., Ajito S., Sato S., Ohta N., Igarashi N., Shimizu N. (2018). Preferential intercalation of human amyloid-β peptide into interbilayer region of lipid-raft membrane in macromolecular crowding environment. J. Phys. Chem. B 122, 9482–9489. 10.1021/acs.jpcb.8b08006 PubMed DOI

Hirai M., Kimura R., Takeuchi K., Sugiyama M., Kasahara K., Ohta N., et al. . (2013). Change of dynamics of raft-model membrane induced by amyloid-β protein binding. Eur. Phys. J. E Soft Matter 36:74. 10.1140/epje/i2013-13074-3 PubMed DOI

Honeycutt J. D., Thirumalai D. (1990). Metastability of the folded states of globular-proteins. Proc. Natl. Acad. Sci. U S A 87, 3526–3529. 10.1073/pnas.87.9.3526 PubMed DOI PMC

Hooijmans C. R., Rutters F., Dederen P. J., Gambarota G., Veltien A., van Groen T., et al. . (2007). Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD). Neurobiol. Dis. 28, 16–29. 10.1016/j.nbd.2007.06.007 PubMed DOI

Hu X. Y., Crick S. L., Bu G. J., Frieden C., Pappu R. V., Lee J. M. (2009). Amyloid seeds formed by cellular uptake, concentration and aggregation of the amyloid-β peptide. Proc. Natl. Acad. Sci. U S A 106, 20324–20329. 10.1073/pnas.0911281106 PubMed DOI PMC

Hu Z. P., Wang X. L., Wang W. R., Zhang Z. L., Gao H. P., Mao Y. L. (2015). Raman spectroscopy for detecting supported planar lipid bilayers composed of ganglioside-GM1/sphingomyelin/cholesterol in the presence of amyloid-β. Phys. Chem. Chem. Phys. 17, 22711–22720. 10.1039/c5cp02366a PubMed DOI

Huang X., Zhen J., Dong S., Zhang H., Van Halm-Lutterodt N., Yuan L. (2019). DHA and vitamin E antagonized the Aβ25–35-mediated neuron oxidative damage through activation of Nrf2 signaling pathways and regulation of CD36, SRB1 and FABP5 expression in PC12 cells. Food Funct. 10, 1049–1061. 10.1039/C8FO01713A PubMed DOI

Hussain G., Wang J., Rasul A., Anwar H., Imran A., Qasim M., et al. . (2019). Role of cholesterol and sphingolipids in brain development and neurological diseases. Lipids Health Dis. 18:26. 10.1186/s12944-019-0965-z PubMed DOI PMC

Igbavboa U., Avdulov N. A., Schroeder F., Wood W. G. (1996). Increasing age alters transbilayer fluidity and cholesterol asymmetry in synaptic plasma membranes of mice. J. Neurochem. 66, 1717–1725. 10.1046/j.1471-4159.1996.66041717.x PubMed DOI

Jack C. R., Knopman D. S., Jagust W. J., Shaw L. M., Aisen P. S., Weiner M. W., et al. . (2010). Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128. 10.1016/S1474-4422(09)70299-6 PubMed DOI PMC

Jamasbi E., Separovic F., Hossain M. A., Ciccotosto G. D. (2017). Phosphorylation of a full length amyloid-β peptide modulates its amyloid aggregation, cell binding and neurotoxic properties. Mol. Biosyst. 13, 1545–1551. 10.1039/c7mb00249a PubMed DOI

Janickova H., Rudajev V., Dolejsi E., Koivisto H., Jakubik J., Tanila H., et al. . (2015). Lipid-based diets improve muscarinic neurotransmission in the hippocampus of transgenic APPswe/PS1dE9 Mice. Curr. Alzheimer Res. 12, 923–931. 10.2174/1567205012666151027130350 PubMed DOI

Jaya Prasanthi R. P., Schommer E., Thomasson S., Thompson A., Feist G., Ghribi O. (2008). Regulation of β-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer’s disease. Mech. Ageing Dev. 129, 649–655. 10.1016/j.mad.2008.09.002 PubMed DOI PMC

Jeong A., Cheng S. W., Zhong R., Bennett D. A., Bergo M. O., Li L. (2021). Protein farnesylation is upregulated in Alzheimer’s human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer’s model mice. Acta Neuropathol. Commun. 9:129. 10.1186/s40478-021-01231-5 PubMed DOI PMC

Ji S. R., Wu Y., Sui S. F. (2002). Cholesterol is an important factor affecting the membrane insertion of β-amyloid peptide (Aβ1-40), which may potentially inhibit the fibril formation. J. Biol. Chem. 277, 6273–6279. 10.1074/jbc.M104146200 PubMed DOI

Jick H., Zornberg G. L., Jick S. S., Seshadri S., Drachman D. A. (2000). Statins and the risk of dementia. Lancet 356, 1627–1631. 10.1016/s0140-6736(00)03155-x PubMed DOI

Jin P., Pan Y. M., Pan Z. Y., Xu J. Q., Lin M., Sun Z. C., et al. . (2018). Alzheimer-like brain metabolic and structural features in cholesterol-fed rabbit detected by magnetic resonance imaging. Lipids Health Dis. 17:61. 10.1186/s12944-018-0705-9 PubMed DOI PMC

Julien C., Tomberlin C., Roberts C. M., Akram A., Stein G. H., Silverman M. A., et al. . (2018). In vivo induction of membrane damage by β-amyloid peptide oligomers. Acta Neuropathol. Commun. 6:131. 10.1186/s40478-018-0634-x PubMed DOI PMC

Jurevics H., Morell P. (1995). Cholesterol for synthesis of myelin is made locally, not imported into brain. J. Neurochem. 64, 895–901. 10.1046/j.1471-4159.1995.64020895.x PubMed DOI

Kakio A., Nishimoto S., Yanagisawa K., Kozutsumi Y., Matsuzaki K. (2001). Cholesterol-dependent formation of GM1 ganglioside-bound amyloid β-protein, an endogenous seed for Alzheimer amyloid. J. Biol. Chem. 276, 24985–24990. 10.1074/jbc.M100252200 PubMed DOI

Kakio A., Nishimoto S., Yanagisawa K., Kozutsumi Y., Matsuzaki K. (2002). Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 41, 7385–7390. 10.1021/bi0255874 PubMed DOI

Kalvodova L., Kahya N., Schwille P., Ehehalt R., Verkade P., Drechsel D., et al. . (2005). Lipids as modulators of proteolytic activity of BACE - involvement of cholesterol, glycosphingolipids and anionic phospholipids in vitro. J. Biol. Chem. 280, 36815–36823. 10.1074/jbc.M504484200 PubMed DOI

Kandel N., Matos J. O., Tatulian S. A. (2019). Structure of amyloid β25-35 in lipid environment and cholesterol-dependent membrane pore formation. Sci. Rep. 9:2689. 10.1038/s41598-019-38749-7 PubMed DOI PMC

Kao Y. C., Ho P. C., Tu Y. K., Jou I. M., Tsai K. J. (2020). Lipids and Alzheimer’s disease. Int. J. Mol. Sci. 21:1505. 10.3390/ijms21041505 PubMed DOI PMC

Karimi H., Dokoohaki M. H., Zolghadr A. R., Ghatee M. H. (2019). The interactions of an Aβ protofibril with a cholesterol-enriched membrane and involvement of neuroprotective carbazolium-based substances. Phys. Chem. Chem. Phys. 21, 11066–11078. 10.1039/c9cp00859d PubMed DOI

Kawarabayashi T., Shoji M., Younkin L. H., Lin W. L., Dickson D. W., Murakami T., et al. . (2004). Dimeric amyloid β protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer’s disease. J. Neurosci. 24, 3801–3809. 10.1523/JNEUROSCI.5543-03.2004 PubMed DOI PMC

Kerr J. S., Adriaanse B. A., Greig N. H., Mattson M. P., Cader M. Z., Bohr V. A., et al. . (2017). Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms. Trends Neurosci. 40, 151–166. 10.1016/j.tins.2017.01.002 PubMed DOI PMC

Kim H. D., Gim J. A., Yeo S. H., Kim H. S. (2017). Integrated late onset alzheimer’s disease (LOAD) susceptibility genes: cholesterol metabolism and trafficking perspectives. Gene 597, 10–16. 10.1016/j.gene.2016.10.022 PubMed DOI

Kim Y., Kim C., Jang H. Y., Mook-Jung I. (2016). Inhibition of cholesterol biosynthesis reduces γ-secretase activity and amyloid-β generation. J. Alzheimers Dis. 51, 1057–1068. 10.3233/JAD-150982 PubMed DOI

Kim S. I., Yi J. S., Ko Y. G. (2006). Amyloid β oligomerization is induced by brain lipid rafts. J. Cell. Biochem. 99, 878–889. 10.1002/jcb.20978 PubMed DOI

Kirsch C., Eckert G. P., Mueller W. E. (2002). Cholesterol attenuates the membrane perturbing properties of β-amyloid peptides. Amyloid 9, 149–159. 10.3109/13506120209114816 PubMed DOI

Kirsch C., Eckert G. P., Mueller W. E. (2003). Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem. Pharmacol. 65, 843–856. 10.1016/s0006-2952(02)01654-4 PubMed DOI

Kivipelto M., Helkala E. L., Hanninen T., Laakso M. P., Hallikainen M., Alhainen K., et al. . (2001). Midlife vascular risk factors and late-life mild cognitive impairment: a longitudinal, population-based study. Neurology 56, 1683–1689. 10.1212/wnl.56.12.1683 PubMed DOI

Kojro E., Gimpl G., Lammich S., Marz W., Fahrenholz F. (2001). Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc. Natl. Acad. Sci. U S A 98, 5815–5820. 10.1073/pnas.081612998 PubMed DOI PMC

Kunkle B. W., Grenier-Boley B., Sims R., Bis J. C., Damotte V., Naj A. C., et al. . (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430. 10.1038/s41588-019-0358-2 PubMed DOI PMC

Kurinami H., Sato N., Shinohara M., Takeuchi D., Takeda S., Shimamura M., et al. . (2008). Prevention of amyloid ss-induced memory impairment by fluvastatin, associated with the decrease in amyloid ss accumulation and oxidative stress in amyloid ss injection mouse model. Int. J. Mol. Med. 21, 531–537. PubMed

Lanfranco M. F., Ng C. A., Rebeck G. W. (2020). ApoE lipidation as a therapeutic target in Alzheimer’s disease. Int. J. Mol. Sci. 21:6336. 10.3390/ijms21176336 PubMed DOI PMC

Lazar A. N., Bich C., Panchal M., Desbenoit N., Petit V. W., Touboul D., et al. . (2013). Time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging reveals cholesterol overload in the cerebral cortex of Alzheimer disease patients. Acta Neuropathol. 125, 133–144. 10.1007/s00401-012-1041-1 PubMed DOI

Ledesma M. D., Abad-Rodriguez J., Galvan C., Biondi E., Navarro P., Delacourte A., et al. . (2003). Raft disorganization leads to reduced plasmin activity in Alzheimer’s disease brains. EMBO Rep. 4, 1190–1196. 10.1038/sj.embor.7400021 PubMed DOI PMC

Ledesma M. D., Martin M. G., Dotti C. G. (2012). Lipid changes in the aged brain: effect on synaptic function and neuronal survival. Prog. Lipid Res. 51, 23–35. 10.1016/j.plipres.2011.11.004 PubMed DOI

Ledreux A., Wang X. Z., Schultzberg M., Granholm A. C., Freeman L. R. (2016). Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats. Behav. Brain Res. 312, 294–304. 10.1016/j.bbr.2016.06.012 PubMed DOI PMC

Lee S. I., Jeong W., Lim H., Cho S., Lee H., Jang Y., et al. . (2021). APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation. Stem Cell Rep. 16, 2128–2137. 10.1016/j.stemcr.2021.07.017 PubMed DOI PMC

Lee J., Kim Y. H., Arce F. T., Gillman A. L., Jang H., Kagan B. L., et al. . (2017). Amyloid β ion channels in a membrane comprising brain total lipid extracts. ACS Chem. Neurosci. 8, 1348–1357. 10.1021/acschemneuro.7b00006 PubMed DOI PMC

Lee S. J., Liyanage U., Bickel P. E., Xia W. M., Lansbury P. T., Kosik K. S. (1998). A detergent-insoluble membrane compartment contains Aβ in vivo. Nat. Med. 4, 730–734. 10.1038/nm0698-730 PubMed DOI

Leoni V., Shafaati M., Salomon A., Kivipelto M., Bjorkhem I., Wahlund L. O. (2006). Are the CSF levels of 24S-hydroxychole sterol a sensitive biomarker for mild cognitive impairment? Neurosci. Lett. 397, 83–87. 10.1016/j.neulet.2005.11.046 PubMed DOI

Leoni V., Solomon A., Kivipelto M. (2010). Links between ApoE, brain cholesterol metabolism, tau and amyloid β-peptide in patients with cognitive impairment. Biochem. Soc. Trans. 38, 1021–1025. 10.1042/BST0381021 PubMed DOI

Liguori N., Nerenberg P. S., Head-Gordon T. (2013). Embedding Aβ42 in heterogeneous membranes depends on cholesterol asymmetries. Biophys. J. 105, 899–910. 10.1016/j.bpj.2013.06.046 PubMed DOI PMC

Lin M. S., Chen L. Y., Wang S. S. S., Chang Y., Chen W. Y. (2008). Examining the levels of ganglioside and cholesterol in cell membrane on attenuation the cytotoxicity of β-amyloid peptide. Colloids Surf. B Biointerfaces 65, 172–177. 10.1016/j.colsurfb.2008.03.012 PubMed DOI

Lin F. C., Chuang Y. S., Hsieh H. M., Lee T. C., Chiu K. F., Liu C. K., et al. . (2015). Early statin use and the progression of Alzheimer disease a total population-based case-control study. Medicine (Baltimore) 94:e2143. 10.1097/MD.0000000000002143 PubMed DOI PMC

Lin M. C. A., Kagan B. L. (2002). Electrophysiologic properties of channels induced by Aβ25–35 in planar lipid bilayers. Peptides 23, 1215–1228. 10.1016/s0196-9781(02)00057-8 PubMed DOI

Lin Y. T., Seo J., Gao F., Feldman H. M., Wen H. L., Penney J., et al. . (2018). APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154. 10.1016/j.neuron.2018.06.011 PubMed DOI PMC

Lingwood D., Simons K. (2010). Lipid rafts as a membrane-organizing principle. Science 327, 46–50. 10.1126/science.1174621 PubMed DOI

Litvinov D. Y., Savushkin E. V., Dergunov A. D. (2018). Intracellular and plasma membrane events in cholesterol transport and homeostasis. J. Lipids 2018:3965054. 10.1155/2018/3965054 PubMed DOI PMC

Liu P., Reed M. N., Kotilinek L. A., Grant M. K. O., Forster C. L., Qiang W., et al. . (2015). Quaternary structure defines a large class of amyloid-β oligomers neutralized by sequestration. Cell Rep. 11, 1760–1771. 10.1016/j.celrep.2015.05.021 PubMed DOI PMC

Liu R. Q., Tian T., Jia J. P. (2015). Characterization of the interactions between β-amyloid peptide and the membranes of human SK-N-SH cells. FEBS Lett. 589, 1929–1934. 10.1016/j.febslet.2015.05.035 PubMed DOI

Loera-Valencia R., Goikolea J., Parrado-Fernandez C., Merino-Serraisa P., Maioli S. (2019). Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: potential novel targets for treatment. J. Steroid Biochem. Mol. Biol. 190, 104–114. 10.1016/j.jsbmb.2019.03.003 PubMed DOI

Malchiodi-Albedi F., Contrusciere V., Raggi C., Fecchi K., Rainaldi G., Paradisi S., et al. . (2010). Lipid raft disruption protects mature neurons against amyloid oligomer toxicity. Biochim. Biophys. Acta 1802, 406–415. 10.1016/j.bbadis.2010.01.007 PubMed DOI

Mao Y. L., Shang Z. G., Imai Y., Hoshino T., Tero R., Tanaka M., et al. . (2010). Surface-induced phase separation of a sphingomyelin/cholesterol/ganglioside GM1-planar bilayer on mica surfaces and microdomain molecular conformation that accelerates Aβ oligomerization. Biochim. Biophy. Acta 1798, 1090–1099. 10.1016/j.bbamem.2010.03.003 PubMed DOI

Marin R., Fabelo N., Martin V., Garcia-Esparcia P., Ferrer I., Quinto-Alemany D., et al. . (2017). Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer’s and Parkinson’s diseases. Neurobiol. Aging 49, 52–59. 10.1016/j.neurobiolaging.2016.08.027 PubMed DOI

Marquer C., Devauges V., Cossec J. C., Liot G., Lecart S., Saudou F., et al. . (2011). Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. FASEB J. 25, 1295–1305. 10.1096/fj.10-168633 PubMed DOI

Marquer C., Laine J., Dauphinot L., Hanbouch L., Lemercier-Neuillet C., Pierrot N., et al. . (2014). Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes. Mol. Neurodegener. 9:60. 10.1186/1750-1326-9-60 PubMed DOI PMC

Martin M., Dotti C. G., Ledesma M. D. (2010). Brain cholesterol in normal and pathological aging. Biochim. Biophys. Acta 1801, 934–944. 10.1016/j.bbalip.2010.03.011 PubMed DOI

Martín V., Fabelo N., Santpere G., Puig B., Marin R., Ferrer I., et al. . (2010). Lipid alterations in lipid rafts from Alzheimer’s disease human brain cortex. J. Alzheimers Dis. 19, 489–502. 10.3233/JAD-2010-1242 PubMed DOI

Martin M. G., Trovo L., Perga S., Sadowska A., Rasola A., Chiara F., et al. . (2011). Cyp46-mediated cholesterol loss promotes survival in stressed hippocampal neurons. Neurobiol. Aging 32, 933–943. 10.1016/j.neurobiolaging.2009.04.022 PubMed DOI

Matsubara T., Nishihara M., Yasumori H., Nakai M., Yanagisawa K., Sato T. (2017). Size and shape of amyloid fibrils induced by ganglioside nanoclusters: role of sialyl oligosaccharide in fibril formation. Langmuir 33, 13874–13881. 10.1021/acs.langmuir.7b02091 PubMed DOI

Matsubara T., Yasumori H., Ito K., Shimoaka T., Hasegawa T., Sato T. (2018). Amyloid- fibrils assembled on ganglioside-enriched membranes contain both parallel -sheets and turns. J. Biol. Chem. 293, 14146–14154. 10.1074/jbc.RA118.002787 PubMed DOI PMC

Matsuzaki K. (2011). Formation of toxic amyloid fibrils by amyloid beta-protein on ganglioside clusters. Int. J. Alzheimers Dis. 2011:956104. 10.4061/2011/956104 PubMed DOI PMC

Matsuzaki K. (2014). How do membranes initiate Alzheimer’s disease? Formation of toxic arnyloid fibrils by the amyloid β-protein on ganglioside clusters. Acc. Chem. Res. 47, 2397–2404. 10.1021/ar500127z PubMed DOI

Matsuzaki K., Horikiri C. (1999). Interactions of amyloid β-peptide (1–40) with ganglioside-containing membranes. Biochemistry 38, 4137–4142. 10.1021/bi982345o PubMed DOI

Maxfield F. R., Wustner D. (2002). Intracellular cholesterol transport. J. Clin. Invest. 110, 891–898. 10.1172/JCI16500 PubMed DOI PMC

McFarlane O., Kedziora-Kornatowska K. (2020). Cholesterol and dementia: a long and complicated relationship. Curr. Aging Sci. 13, 42–51. 10.2174/1874609812666190917155400 PubMed DOI PMC

Meleleo D., Galliani A., Notarachille G. (2013). AβP1–42 incorporation and channel formation in planar lipid membranes: the role of cholesterol and its oxidation products. J. Bioenerg. Biomembr. 45, 369–381. 10.1007/s10863-013-9513-0 PubMed DOI

Meleleo D., Notarachille G., Mangini V., Arnesano F. (2019). Concentration-dependent effects of mercury and lead on A42: possible implications for Alzheimer’s disease. Eur. Biophys. J. 48, 173–187. 10.1007/s00249-018-1344-9 PubMed DOI

Micelli S., Meleleo D., Picciarelli V., Gallucci E. (2004). Effect of sterols on β-amyloid peptide (AβP 1-40) channel formation and their properties in planar lipid membranes. Biophys. J. 86, 2231–2237. 10.1016/S0006-3495(04)74281-2 PubMed DOI PMC

Mielke M. M., Zandi P. P., Sjogren M., Gustafson D., Ostling S., Steen B., et al. . (2005). High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 64, 1689–1695. 10.1212/01.WNL.0000161870.78572.A5 PubMed DOI

Mizuno T., Nakata M., Naiki H., Michikawa M., Wang R., Haass C., et al. . (1999). Cholesterol-dependent generation of a seeding amyloid β-protein in cell culture. J. Biol. Chem. 274, 15110–15114. 10.1074/jbc.274.21.15110 PubMed DOI

Mohamed A., Viveiros A., Williams K., de Chaves E. P. (2018). Aβ inhibits SREBP-2 activation through Akt inhibition. J. Lipid Res. 59, 1–13. 10.1194/jlr.M076703 PubMed DOI PMC

Molander-Melin M., Blennow K., Bogdanovic N., Dellheden B., Mansson J. E., Fredman P. (2005). Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent-resistant membrane domains. J. Neurochem. 92, 171–182. 10.1111/j.1471-4159.2004.02849.x PubMed DOI

Montesinos J., Pera M., Larrea D., Guardia-Laguarta C., Agrawal R. R., Velasco K. R., et al. . (2020). The Alzheimer’s disease-associated C99 fragment of APP regulates cellular cholesterol trafficking. EMBO J. 39:e103791. 10.15252/embj.2019103791 PubMed DOI PMC

Mori K., Mahmood M. I., Neya S., Matsuzaki K., Hoshino T. (2012). Formation of GM1 ganglioside clusters on the lipid membrane containing sphingomyeline and cholesterol. J. Phys. Chem. B 116, 5111–5121. 10.1021/jp207881k PubMed DOI

Morrow J. A., Hatters D. M., Lu B., Hochtl P., Oberg K. A., Rupp B., et al. . (2002). Apolipoprotein E4 forms a molten globule - a potential basis for its association with disease. J. Biol. Chem. 277, 50380–50385. 10.1074/jbc.M204898200 PubMed DOI

Narayan P., Holmstrom K. M., Kim D. H., Whitcomb D. J., Wilson M. R., George-Hyslop P. S., et al. . (2014). Rare individual amyloid-β oligomers act on astrocytes to initiate neuronal damage. Biochemistry 53, 2442–2453. 10.1021/bi401606f PubMed DOI PMC

Naudi A., Cabre R., Jove M., Ayala V., Gonzalo H., Portero-Otin M., et al. . (2015). Lipidomics of human brain aging and Alzheimer’s disease pathology. Int. Rev. Neurobiol. 122, 133–189. 10.1016/bs.irn.2015.05.008 PubMed DOI

Nicastro M. C., Spigolon D., Librizzi F., Moran O., Ortore M. G., Bulone D., et al. . (2016). Amyloid β-peptide insertion in liposomes containing GM1-cholesterol domains. Biophys. Chem. 208, 9–16. 10.1016/j.bpc.2015.07.010 PubMed DOI

Nicholson A. M., Ferreira A. (2009). Increased membrane cholesterol might render mature hippocampal neurons more susceptible to β-amyloid-induced calpain activation and tau toxicity. J. Neurosci. 29, 4640–4651. 10.1523/JNEUROSCI.0862-09.2009 PubMed DOI PMC

Nierzwicki L., Olewniczak M., Chodnicki P., Czub J. (2021). Role of cholesterol in substrate recognition by γ-secretase. Sci. Rep. 11:15213. 10.1038/s41598-021-94618-2 PubMed DOI PMC

Nilsson N. I. V., Picard C., Labonte A., Kobe T., Meyer P. F., Villeneuve S., et al. . (2021). Association of a total cholesterol polygenic score with cholesterol levels and pathological biomarkers across the Alzheimer’s disease spectrum. Genes (Basel) 12:1805. 10.3390/genes12111805 PubMed DOI PMC

Oikawa N., Hatsuta H., Murayama S., Suzuki A., Yanagisawa K. (2014). Influence of APOE genotype and the presence of Alzheimer’s pathology on synaptic membrane lipids of human brains. J. Neurosci. Res. 92, 641–650. 10.1002/jnr.23341 PubMed DOI

Okada T., Ikeda K., Wakabayashi M., Ogawa M., Matsuzaki K. (2008). Formation of toxic Aβ(1-40) fibrils on GM1 ganglioside-containing membranes mimicking lipid rafts: polymorphisms in Aβ(1–40) fibrils. J. Mol. Biol. 382, 1066–1074. 10.1016/j.jmb.2008.07.072 PubMed DOI

Oksman M., Iivonen H., Hogyes E., Amtul Z., Penke B., Leenders I., et al. . (2006). Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on β-amyloid accumulation in APP/PS1 transgenic mice. Neurobiol. Dis. 23, 563–572. 10.1016/j.nbd.2006.04.013 PubMed DOI

Oku Y., Murakami K., Irie K., Hoseki J., Sakai Y. (2017). Synthesized Aβ42 caused intracellular oxidative damage, leading to cell death, via lysosome rupture. Cell Struct. Funct. 42, 71–79. 10.1247/csf.17006 PubMed DOI

Ong W. Y., Kim J. H., He X., Chen P., Farooqui A. A., Jenner A. M. (2010). Changes in brain cholesterol metabolome after excitotoxicity. Mol. Neurobiol. 41, 299–313. 10.1007/s12035-010-8099-3 PubMed DOI

Osenkowski P., Ye W., Wang R., Wolfe M. S., Selkoe D. J. (2008). Direct and potent regulation of γ-secretase by its lipid microenvironment. J. Biol. Chem. 283, 22529–22540. 10.1074/jbc.M801925200 PubMed DOI PMC

Ostrowski S. M., Wilkinson B. L., Golde T. E., Landreth G. (2007). Statins reduce amyloid-β production through inhibition of protein isoprenylation. J. Biol. Chem. 282, 26832–26844. 10.1074/jbc.M702640200 PubMed DOI

Ott B. R., Daiello L. A., Dahabreh I. J., Springate B. A., Bixby K., Murali M., et al. . (2015). Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J. Gen. Int. Med. 30, 348–358. 10.1007/s11606-014-3115-3 PubMed DOI PMC

Owen M. C., Kulig W., Poojari C., Rog T., Strodel B. (2018). Physiologically-relevant levels of sphingomyelin, but not GM1, induces a β-sheet-rich structure in the amyloid-β(1–42) monomer. Biochim. Biophys Acta Biomembr. 1860, 1709–1720. 10.1016/j.bbamem.2018.03.026 PubMed DOI

Panahi A., Bandara A., Pantelopulos G. A., Dominguez L., Straub J. E. (2016). Specific binding of cholesterol to C99 domain of amyloid precursor protein depends critically on charge state of protein. J. Phys. Chem. Lett. 7, 3535–3541. 10.1021/acs.jpclett.6b01624 PubMed DOI PMC

Panchal M., Loeper J., Cossec J. C., Perruchini C., Lazar A., Pompon D., et al. . (2010). Enrichment of cholesterol in microdissected Alzheimer’s disease senile plaques as assessed by mass spectrometry. J. Lipid Res. 51, 598–605. 10.1194/jlr.M001859 PubMed DOI PMC

Pannuzzo M. (2016). On the physiological/pathological link between Aβ peptide, cholesterol, calcium ions and membrane deformation: a molecular dynamics study. Biochim. Biophys. Acta 1858, 1380–1389. 10.1016/j.bbamem.2016.03.018 PubMed DOI

Pantelopulos G. A., Panahi A., Straub J. E. (2020). Impact of cholesterol concentration and lipid phase on structure and fluctuation of amyloid precursor protein. J. Phys. Chem. B. 124, 10173–10185. 10.1021/acs.jpcb.0c07615 PubMed DOI PMC

Panza F., D’Introno A., Colacicco A. M., Capurso C., Pichichero G., Capurso S. A., et al. . (2006). Lipid metabolism in cognitive decline and dementia. Brain Res. Rev. 51, 275–292. 10.1016/j.brainresrev.2005.11.007 PubMed DOI

Pedrini S., Carter T. L., Prendergast G., Petanceska S., Ehrlich M. E., Gandy S. (2005). Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med. 2, 69–78. 10.1371/journal.pmed.0020018 PubMed DOI PMC

Peters I., Igbavboa U., Schutt T., Haidari S., Hartig U., Rosello X., et al. . (2009). The interaction of β-amyloid protein with cellular membranes stimulates its own production. Biochim. Biophys. Acta 1788, 964–972. 10.1016/j.bbamem.2009.01.012 PubMed DOI PMC

Petrov A. M., Kasimov M. R., Zefirov A. L. (2016). Brain cholesterol metabolism and its defects: linkage to neurodegenerative diseases and synaptic dysfunction. Acta Naturae 8, 58–73. PubMed PMC

Phan H. T., Hata T., Morita M., Yoda T., Hamada T., Vestergaard M. C., et al. . (2013). The effect of oxysterols on the interaction of Alzheimer’s amyloid β with model membranes. Biochim. Biophys. Acta 1828, 2487–2495. 10.1016/j.bbamem.2013.06.021 PubMed DOI

Phan H. T. T., Shimokawa N., Sharma N., Takagi M., Vestergaard M. C. (2018). Strikingly different effects of cholesterol and 7-ketocholesterol on lipid bilayer-mediated aggregation of amyloid β (1–42). Biochem. Biophys. Rep. 14, 98–103. 10.1016/j.bbrep.2018.04.007 PubMed DOI PMC

Phan H. T. T., Vestergaard M. C., Baek K., Shimokawa N., Takagi M. (2014). Localization of amyloid β (Aβ1–42) protofibrils in membrane lateral compartments: effect of cholesterol and 7-Ketocholesterol. FEBS Lett. 588, 3483–3490. 10.1016/j.febslet.2014.08.007 PubMed DOI

Pierrot N., Tyteca D., D’auria L., Dewachter I., Gailly P., Hendrickx A., et al. . (2013). Amyloid precursor protein controls cholesterol turnover needed for neuronal activity. EMBO Mol. Med. 5, 608–625. 10.1002/emmm.201202215 PubMed DOI PMC

Pimenova A. A., Raj T., Goate A. M. (2018). untangling genetic risk for Alzheimer’s disease. Biol. Psych. 83, 300–310. 10.1016/j.biopsych.2017.05.014 PubMed DOI PMC

Pincon A., Thomas M. H., Huguet M., Allouche A., Colin J. C., Georges A., et al. . (2015). Increased susceptibility of dyslipidemic LSR+/– mice to amyloid stress is associated with changes in cortical cholesterol levels. J. Alzheimers Dis. 45, 195–204. 10.3233/JAD-142127 PubMed DOI

Prangkio P., Yusko E. C., Sept D., Yang J., Mayer M. (2012). Multivariate analyses of amyloid-β oligomer populations indicate a connection between pore formation and cytotoxicity. PLoS One 7:e47261. 10.1371/journal.pone.0047261 PubMed DOI PMC

Press-Sandler O., Miller Y. (2018). Molecular mechanisms of membrane-associated amyloid aggregation: computational perspective and challenges. Biochim. Biophys. Acta-Biomembr. 1860, 1889–1905. 10.1016/j.bbamem.2018.03.014 PubMed DOI

Qiu L., Buie C., Reay A., Vaughn M. W., Cheng K. H. (2011). Molecular dynamics simulations reveal the protective role of cholesterol in β-amyloid protein-induced membrane disruptions in neuronal membrane mimics. J. Phys. Chem. B. 115, 9795–9812. 10.1021/jp2012842 PubMed DOI PMC

Qiu L., Lewis A., Como J., Vaughn M. W., Huang J., Somerharju P., et al. . (2009). Cholesterol modulates the interaction of β-amyloid peptide with lipid bilayers. Biophys. J. 96, 4299–4307. 10.1016/j.bpj.2009.02.036 PubMed DOI PMC

Qu L., Fudo S., Matsuzaki K., Hoshino T. (2019). Computational study on the assembly of amyloid β-peptides in the hydrophobic environment. Chem. Pharm. Bull. (Tokyo) 67, 959–965. 10.1248/cpb.c19-00171 PubMed DOI

Reitz C. (2013). Dyslipidemia and the risk of Alzheimer’s disease. Curr. Atheroscler. Rep. 15:307. 10.1007/s11883-012-0307-3 PubMed DOI PMC

Ricciarelli R., Canepa E., Marengo B., Marinari U. M., Poli G., Pronzato M. A., et al. . (2012). Cholesterol and Alzheimer’s disease: a still poorly understood correlation. IUBMB Life 64, 931–935. 10.1002/iub.1091 PubMed DOI

Roca-Agujetas V., Barbero-Camps E., de Dios C., Podlesniy P., Abadin X., Morales A., et al. . (2021). Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer’s disease. Mol. Neurodegen. 16:15. 10.1186/s13024-021-00435-6 PubMed DOI PMC

Rondelli V., Salmona M., Colombo L., Fragneto G., Fadda G. C., Cantu L., et al. . (2020). Aβ beyond the AD pathology: exploring the structural response of membranes exposed to nascent Aβ peptide. Int. J. Mol. Sci. 21:8295. 10.3390/ijms21218295 PubMed DOI PMC

Rudajev V., Novotny J. (2020). The role of lipid environment in ganglioside GM1-induced amyloid β aggregation. Membranes (Basel) 10:226. 10.3390/membranes10090226 PubMed DOI PMC

Ruiz-Arias A., Paredes J. M., Di Biase C., Cuerva J. M., Giron M. D., Salto R., et al. . (2020). Seeding and growth of β-amyloid aggregates upon interaction with neuronal cell membranes. Int. J. Mol. Sci. 21:5035. 10.3390/ijms21145035 PubMed DOI PMC

Runz H., Rietdorf J., Tomic I., de Bernard M., Beyreuther K., Pepperkok R., et al. . (2002). Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J. Neurosci. 22, 1679–1689. 10.1523/JNEUROSCI.22-05-01679.2002 PubMed DOI PMC

Rushworth J. V., Hooper N. M. (2010). Lipid rafts: linking Alzheimer’s amyloid-β production, aggregation and toxicity at neuronal membranes. Int. J. Alzheimers Dis. 2011:603052. 10.4061/2011/603052 PubMed DOI PMC

Sathya M., Moorthi P., Premkumar P., Kandasamy M., Jayachandran K. S., Anusuyadevi M. (2017). Resveratrol intervenes cholesterol- and isoprenoid-mediated amyloidogenic processing of AβPP in familial Alzheimer’s disease. J. Alzheimers Dis. 60, S3–S23. 10.3233/JAD-161034 PubMed DOI

Schilling S., Tzourio C., Soumare A., Kaffashian S., Dartigues J. F., Ancelin M. L., et al. . (2017). Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: a longitudinal, population-based prospective cohort study. PLoS Med. 14:e1002265. 10.1371/journal.pmed.1002265 PubMed DOI PMC

Schneider A., Schulz-Schaeffer W., Hartmann T., Schulz J. B., Simons M. (2006). Cholesterol depletion reduces aggregation of amyloid-beta peptide in hippocampal neurons. Neurobiol. Dis. 23, 573–577. 10.1016/j.nbd.2006.04.015 PubMed DOI

Schultz B. G., Patten D. K., Berlau D. J. (2018). The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Transl. Neurodegen. 7:5. 10.1186/s40035-018-0110-3 PubMed DOI PMC

Sciacca M. F. M., Tempra C., Scollo F., Milardi D., La Rosa C. (2018). Amyloid growth and membrane damage: current themes and emerging perspectives from theory and experiments on Aβ and hIAPP. Biochim. Biophys. Acta Biomembr. 1860, 1625–1638. 10.1016/j.bbamem.2018.02.022 PubMed DOI

Seghezza S., Diaspro A., Canale C., Dante S. (2014). Cholesterol drives Aβ(1–42) interaction with lipid rafts in model membranes. Langmuir 30, 13934–13941. 10.1021/la502966m PubMed DOI

Serra-Batiste M., Ninot-Pedrosa M., Bayoumi M., Gairi M., Maglia G., Carulla N. (2016). Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments. Proc. Natl. Acad. Sci. U S A 113, 10866–10871. 10.1073/pnas.1605104113 PubMed DOI PMC

Shie F. S., Jin L. W., David G. C., Leverenz J. B., LeBoeuf R. C. (2002). Diet-induced hypercholesterolemia enhances brain Aβ accumulation in transgenic mice. Neuroreport 13, 455–459. 10.1097/00001756-200203250-00019 PubMed DOI

Silva T., Teixeira J., Remiao F., Borges F. (2013). Alzheimer’s disease, cholesterol and statins: the junctions of important metabolic pathways. Angew. Chem.-Int. Ed. 52, 1110–1121. 10.1002/anie.201204964 PubMed DOI

Simmons C., Ingham V., Williams A., Bate C. (2014). Platelet-activating factor antagonists enhance intracellular degradation of amyloid-β42 in neurons via regulation of cholesterol ester hydrolases. Alzheimers Res. Ther. 6:15. 10.1186/alzrt245 PubMed DOI PMC

Simons K., Toomre D. (2000). Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39. 10.1038/35036052 PubMed DOI

Smeralda W., Since M., Cardin J., Corvaisier S., Lecomte S., Cullin C., et al. . (2021). Beta-amyloid peptide interactions with biomimetic membranes: a multiparametric characterization. Int. J. Biol Macromol. 181, 769–777. 10.1016/j.ijbiomac.2021.03.107 PubMed DOI

Sokolova T. V., Zakharova I. O., Furaev V. V., Rychkova M. P., Avrova N. F. (2007). Neuroprotective effect of ganglioside GM1 on the cytotoxic action of hydrogen peroxide and amyloid β-peptide in PC12 cells. Neurochem. Res. 32, 1302–1313. 10.1007/s11064-007-9304-2 PubMed DOI

Solomon A., Kivipelto M., Wolozin B., Zhou J. F., Whitmer R. A. (2009). Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement. Geriatr. Cogn. Dis. 28, 75–80. 10.1159/000231980 PubMed DOI PMC

Srivastava A. K., Pittman J. M., Zerweck J., Venkata B. S., Moore P. C., Sachleben J. R., et al. . (2019). β-amyloid aggregation and heterogeneous nucleation. Protein Sci. 28, 1567–1581. 10.1002/pro.3674 PubMed DOI PMC

Staneva G., Puff N., Stanimirov S., Tochev T., Angelova M. I., Seigneuret M. (2018). The Alzheimer’s disease amyloid-β peptide affects the size-dynamics of raft-mimicking Lo domains in GM1-containing lipid bilayers. Soft Matter 14, 9609–9618. 10.1039/c8sm01636d PubMed DOI

Stewart R., White L. R., Xue Q. L., Launer L. J. (2007). Twenty-six-year change in total cholesterol levels and incident dementia - the honolulu-asia aging study. Arch. Neurol. 64, 103–107. 10.1001/archneur.64.1.103 PubMed DOI

Straub J. E., Thirumalai D. (2014). Membrane-protein interactions are key to understanding amyloid formation. J. Phys. Chem. Lett. 5, 633–635. 10.1021/jz500054d PubMed DOI

Subtil A., Gaidarov I., Kobylarz K., Lampson M. A., Keen J. H., McGraw T. E. (1999). Acute cholesterol depletion inhibits clathrin-coated pit budding. Proc. Natl. Acad. Sci. U S A 96, 6775–6780. 10.1073/pnas.96.12.6775 PubMed DOI PMC

Sun F. D., Chen L., Wei P., Chai M. Y., Ding X. F., Xu L. D., et al. . (2017). Dimerization and structural stability of amyloid precursor proteins affected by the membrane microenvironments. J. Chem. Inf. Model. 57, 1375–1387. 10.1021/acs.jcim.7b00196 PubMed DOI

Sun J. H., Yu J. T., Tan L. (2015). The role of cholesterol metabolism in Alzheimer’s disease. Mol. Neurobiol. 51, 947–965. 10.1007/s12035-014-8749-y PubMed DOI

Svennerholm L. (1994). Gangliosides - a new therapeutic agent against stroke and Alzheimers-disease. Life Sci. 55, 2125–2134. 10.1016/0024-3205(94)00393-9 PubMed DOI

Svennerholm L., Brane G., Karlsson I., Lekman A., Ramstrom I., Wikkelso C. (2002). Alzheimer disease - effect of continuous intracerebroventricular treatment with GM1 ganglioside and a systematic activation programme. Dement. Geriatr. Cogn. Dis. 14, 128–136. 10.1159/000063604 PubMed DOI

Tai L. M., Bilousova T., Jungbauer L., Roeske S. K., Youmans K. L., Yu C. J., et al. . (2013). Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J. Biol. Chem. 288, 5914–5926. 10.1074/jbc.M112.442103 PubMed DOI PMC

Takamori S., Holt M., Stenius K., Lemke E. A., Gronborg M., Riedel D., et al. . (2006). Molecular anatomy of a trafficking organelle. Cell 127, 831–846. 10.1016/j.cell.2006.10.030 PubMed DOI

Takeuchi S., Ueda N., Suzuki K., Shimozawa N., Yasutomi Y., Kimura N. (2019). Elevated membrane cholesterol disrupts lysosomal degradation to induce β-amyloid accumulation the potential mechanism underlying augmentation of β-amyloid pathology by type 2 diabetes mellitus. Am. J. Pathol. 189, 391–404. 10.1016/j.ajpath.2018.10.011 PubMed DOI

Tarawneh R., Holtzman D. M. (2012). The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harbor Persp. Med. 2:a006148. 10.1101/cshperspect.a006148 PubMed DOI PMC

Terakawa M. S., Lin Y., Kinoshita M., Kanemura S., Itoh D., Sugiki T., et al. . (2018). Impact of membrane curvature on amyloid aggregation. Biochim. Biophys. Acta Biomembr. 1860, 1741–1764. 10.1016/j.bbamem.2018.04.012 PubMed DOI PMC

Testa G., Staurenghi E., Zerbinati C., Gargiulo S., Iuliano L., Giaccone G., et al. . (2016). Changes in brain oxysterols at different stages of Alzheimer’s disease: their involvement in neuroinflammation. Redox Biol. 10, 24–33. 10.1016/j.redox.2016.09.001 PubMed DOI PMC

Tonnies E., Trushina E. (2017). Oxidative stress, synaptic dysfunction and Alzheimer’s disease. J. Alzheimers Dis. 57, 1105–1121. 10.3233/JAD-161088 PubMed DOI PMC

Tran M., Reddy P. H. (2021). Defective autophagy and mitophagy in aging and Alzheimer’s disease. Front. Neurosci. 14:612757. 10.3389/fnins.2020.612757 PubMed DOI PMC

Umeda T., Tomiyama T., Kitajima E., Idomoto T., Nomura S., Lambert M. P., et al. . (2012). Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer’s disease model mice. Life Sci. 91, 1169–1176. 10.1016/j.lfs.2011.12.022 PubMed DOI

van der Kant R., Goldstein L. S. B., Ossenkoppele R. (2020). Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat. Rev. Neurosci. 21, 21–35. 10.1038/s41583-019-0240-3 PubMed DOI

Varma V. R., Luleci H. B., Oommen A. M., Varma S., Blackshear C. T., Griswold M. E., et al. . (2021). Abnormal brain cholesterol homeostasis in Alzheimer’s disease-a targeted metabolomic and transcriptomic study. NPJ Aging Mech. Dis. 7:11. 10.1038/s41514-021-00064-9 PubMed DOI PMC

Venko K., Novic M., Stoka V., Zerovnik E. (2021). Prediction of transmembrane regions, cholesterol and ganglioside binding sites in amyloid-forming proteins indicate potential for amyloid pore formation. Front. Mol. Neurosci. 14:619496. 10.3389/fnmol.2021.619496 PubMed DOI PMC

Viani P., Cervato G., Fiorilli A., Cestaro B. (1991). Age-related differences in synaptosomal peroxidative damage and membrane properties. J. Neurochem. 56, 253–258. 10.1111/j.1471-4159.1991.tb02589.x PubMed DOI

Villemagne V. L., Burnham S., Bourgeat P., Brown B., Ellis K. A., Salvado O., et al. . (2013). Amyloid β deposition, neurodegeneration and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 12, 357–367. 10.1016/S1474-4422(13)70044-9 PubMed DOI

Vogels T., Leuzy A., Cicognola C., Ashton N. J., Smolek T., Novak M., et al. . (2020). Propagation of tau pathology: integrating insights from postmortem and in vivo studies. Biol. Psych. 87, 808–818. 10.1016/j.biopsych.2019.09.019 PubMed DOI

von Arnim C. A. F., von Einem B., Weber P., Wagner M., Schwanzar D., Spoelgen R., et al. . (2008). Impact of cholesterol level upon APP and BACE proximity and APP cleavage. Biochem. Biophys. Res. Commun. 370, 207–212. 10.1016/j.bbrc.2008.03.047 PubMed DOI

Vona R., Iessi E., Matarrese P. (2021). Role of cholesterol and lipid rafts in cancer signaling: a promising therapeutic opportunity? Front. Cell. Dev. Biol. 9:622908. 10.3389/fcell.2021.622908 PubMed DOI PMC

Wahrle S., Das P., Nyborg A. C., McLendon C., Shoji M., Kawarabayashi T., et al. . (2002). Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis. 9, 11–23. 10.1006/nbdi.2001.0470 PubMed DOI

Wang S. S. S., Rymer D. L., Good T. A. (2001). Reduction in cholesterol and sialic acid content protects cells from the toxic effects of β-amyloid peptides. J. Bio. Chem. 276, 42027–42034. 10.1074/jbc.M102834200 PubMed DOI

Wang P., Zhang H. H., Wang Y., Zhang M., Zhou Y. Y. (2020). Plasma cholesterol in Alzheimer’s disease and frontotemporal dementia. Transl. Neurosci. 11, 116–123. 10.1515/tnsci-2020-0098 PubMed DOI PMC

West E., Osborne C., Bate C. (2017). The cholesterol ester cycle regulates signalling complexes and synapse damage caused by amyloid-β. J. Cell Sci. 130, 3050–3059. 10.1242/jcs.205484 PubMed DOI

Wiatrak B., Piasny J., Kuzniarski A., Gasiorowski K. (2021). Interactions of amyloid-β with membrane proteins. Int. J. Mol. Sci. 22:6075. 10.3390/ijms22116075 PubMed DOI PMC

Wieckowska-Gacek A., Mietelska-Porowska A., Chutoranski D., Wydrych M., Dlugosz J., Wojda U. (2021). Western diet induces impairment of liver-brain axis accelerating neuroinflammation and amyloid pathology in Alzheimer’s disease. Front. Aging Neurosci. 13:654509. 10.3389/fnagi.2021.654509 PubMed DOI PMC

Williams T. L., Day I. J., Serpell L. C. (2010). The effect of Alzheimer’s Aβ aggregation state on the permeation of biomimetic lipid vesicles. Langmuir 26, 17260–17268. 10.1021/la101581g PubMed DOI

Williams D. M., Finan C., Schmidt A. F., Burgess S., Hingorani A. D. (2020). Lipid lowering and Alzheimer disease risk: a mendelian randomization study. Ann. Neurol. 87, 30–39. 10.1002/ana.25642 PubMed DOI PMC

Williams T. L., Serpell L. C. (2011). Membrane and surface interactions of Alzheimer’s Aβ peptide - insights into the mechanism of cytotoxicity. FEBS J. 278, 3905–3917. 10.1111/j.1742-4658.2011.08228.x PubMed DOI

Wolozin B., Kellman W., Ruosseau P., Celesia G. G., Siegel G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–1443. 10.1001/archneur.57.10.1439 PubMed DOI

Won J. S., Im Y. B., Khan M., Contreras M., Singh A. K., Singh I. (2008). Lovastatin inhibits amyloid precursor protein (APP) β-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts. J. Neurochem. 105, 1536–1549. 10.1111/j.1471-4159.2008.05283.x PubMed DOI PMC

Wood W. G., Li L., Muller W. E., Eckert G. P. (2014). Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. J. Neurochem. 129, 559–572. 10.1111/jnc.12637 PubMed DOI PMC

Wood W. G., Schroeder F., Hogy L., Rao A. M., Nemecz G. (1990). Asymmetric distribution of a fluorescent sterol in synaptic plasma membranes: effects of chronic ethanol consumption. Biochim. Biophys. Acta 1025, 243–246. 10.1016/0005-2736(90)90103-u PubMed DOI

Wood W. G., Schroeder F., Igbavboa U., Avdulov N. A., Chochina S. V. (2002). Brain membrane cholesterol domains, aging and amyloid beta-peptides. Neurobiol. Aging 23, 685–694. 10.1016/s0197-4580(02)00018-0 PubMed DOI

Wood W. G., Strong R., Williamson L. S., Wise R. W. (1984). Changes in lipid composition of cortical synaptosomes from different age groups of mice. Life Sci. 35, 1947–1952. 10.1016/0024-3205(84)90475-2 PubMed DOI

Wu C. W., Liao P. C., Lin C., Kuo C. J., Chen S. T., Chen H. I., et al. . (2003). Brain region-dependent increases in β-amyloid and apolipoprotein E levels in hypercholesterolemic rabbits. J. Neural Transm. 110, 641–649. 10.1007/s00702-002-0809-1 PubMed DOI

Xin Y., Zhang L., Hu J. Y., Gao H. Z., Zhang B. A. (2021). Correlation of early cognitive dysfunction with inflammatory factors and metabolic indicators in patients with Alzheimer’s disease. Am. J. Transl. Res. 13, 9208–9215. PubMed PMC

Xiong H. Q., Callaghan D., Jones A., Walker D. G., Lue L. F., Beach T. G., et al. . (2008). Cholesterol retention in Alzheimer’s brain is responsible for high β- and γ-secretase activities and Aβ production. Neurobiol. Dis. 29, 422–437. 10.1016/j.nbd.2007.10.005 PubMed DOI PMC

Xuan K., Zhao T. M., Qu G. B., Liu H. X., Chen X., Sun Y. H. (2020). The efficacy of statins in the treatment of Alzheimer’s disease: a meta-analysis of randomized controlled trial. Neurol. Sci. 41, 1391–1404. 10.1007/s10072-020-04243-6 PubMed DOI

Yaffe K., Barrett-Connor E., Lin F., Grady D. (2002). Serum lipoprotein levels, statin use and cognitive function in older women. Arch. Neurol. 59, 378–384. 10.1001/archneur.59.3.378 PubMed DOI

Yahi N., Aulas A., Fantini J. (2010). How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer’s β amyloid peptide (Aβ1–40). PLoS One 5:e9079. 10.1371/journal.pone.0009079 PubMed DOI PMC

Yanagisawa K. (2005). Cholesterol and amyloid β fibrillogenesis. Subcell. Biochem. 38, 179–202. 10.1007/0-387-23226-5_9 PubMed DOI

Yang X., Sheng W., Sun G. Y., Lee J. C.-M. (2011). Effects of fatty acid unsaturation numbers on membrane fluidity and α-secretase-dependent amyloid precursor protein processing. Neurochem. Int. 58, 321–329. 10.1016/j.neuint.2010.12.004 PubMed DOI PMC

Yang D. S., Stavrides P., Kumar A., Jiang Y., Mohan P. S., Ohno M., et al. . (2017). Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice. Hum. Mol. Gen. 26, 843–859. 10.1093/hmg/ddx001 PubMed DOI PMC

Yao J. Q., Ho D., Calingasan N. Y., Pipalia N. H., Lin M. T., Beal M. F. (2012). Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J. Exp. Med. 209, 2501–2513. 10.1084/jem.20121239 PubMed DOI PMC

Yip C. M., Darabie A. A., McLaurin J. (2002). Aβ 42-peptide assembly on lipid Bilayers. J. Mol. Biol. 318, 97–107. 10.1016/S0022-2836(02)00028-1 PubMed DOI

Yip C. M., Elton E. A., Darabie A. A., Morrison M. R., McLaurin J. (2001). Cholesterol, a modulator of membrane-associated Aβ-fibrillogenesis and neurotoxicity. J. Mol. Biol. 311, 723–734. 10.1006/jmbi.2001.4881 PubMed DOI

Youmans K. L., Tai L. M., Nwabuisi-Heath E., Jungbauer L., Kanekiyo T., Gan M., et al. . (2012). APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease. J. Biol. Chem. 287, 41774–41786. 10.1074/jbc.M112.407957 PubMed DOI PMC

Yu X., Zheng J. (2012). Cholesterol promotes the interaction of Alzheimer β-amyloid monomer with lipid bilayer. J. Mol. Biol. 421, 561–571. 10.1016/j.jmb.2011.11.006 PubMed DOI

Yuyama K., Yanagisawa K. (2009). Late endocytic dysfunction as a putative cause of amyloid fibril formation in Alzheimer’s disease. J. Neurochem. 109, 1250–1260. 10.1111/j.1471-4159.2009.06046.x PubMed DOI

Zhang Y. P., Brown R. E., Zhang P. C., Zhao Y. T., Ju X. H., Song C. (2018). DHA, EPA and their combination at various ratios differently modulated Aβ25–35-induced neurotoxicity in SH-SY5Y cells. Prostaglandins Leukot. Essent. Fatty Acids 136, 85–94. 10.1016/j.plefa.2017.07.003 PubMed DOI

Zhao L. N., Chiu S. W., Benoit J., Chew L. Y., Mu Y. (2011). Amyloid β peptides aggregation in a mixed membrane bilayer: a molecular dynamics study. J. Phys. Chem. B. 115, 12247–12256. 10.1021/jp2065985 PubMed DOI

Different amyloid β42 preparations induce different cell death pathways in the model of SH-SY5Y neuroblastoma cells

Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol

Modulation of Muscarinic Signalling in the Central Nervous System by Steroid Hormones and Neurosteroids